A receptor protein on the surface of a cell has a binding site with a high affinity for a particular signaling substance (a hormone, pheromone, neurotransmitter, etc.). The specific signaling substance is often referred to as the ligand, a substance that binds to or fits in a site, the ligand binding site. When the signaling substance binds to a receptor, a receptor-ligand complex initiates a sequence or cascade of reactions that changes the function of the cell. A cell surface receptor polypeptide typically comprises an extracellular part which comprises a binding site where the ligand can interact, a transmembrane part that locates a receptor in the cell membrane, and an intracellular part that plays a role in transducing a signal further into the cell once a ligand has bound. A receptor polypeptide can span the cell membrane several times resulting in multiple extra- and intracellular domains.
The response of a cell or tissue to, for example, specific hormones is dictated by the particular receptors it possesses and by the intra- or intercellular reactions initiated by the binding of any one hormone to its receptor. One cell may have two or more types of receptors or various cell types may have different sets of receptors for the same ligand, each of which induces a different response, or the same receptor may occur on various cell types, and binding of the said ligand may trigger a different response in each type of cells. Clearly, different cells respond in a variety of ways to the same ligand, depending on a receptor or its interaction with the cell.
A wide variety of receptors specific for a wealth of ligands exists. Examples can be found among ion-channels, such as Ca+-channels, or Cl−-channels or Na+-channels, glucose transporters; among immunoglobulin receptors, such as IgE receptors; among cytokine receptors; among multi-drug transporters, and so on. “Receptors,” as defined herein, relate to signal-transducing molecules in the broadest sense. These transducing molecules include ion pump-like proteins. For example, the above-mentioned ion channels that transport the ligand (here the ion) through the membrane include receptors that bind to a ligand (eliciting a signal over the membrane) but that do not transport the ligand itself through the membrane, include transport proteins, and include enzymes that act upon contact with a substrate. As an example, receptors having a hormone as a ligand are herein discussed in more detail; however, physiological mechanisms regulating hormone receptor availability and signal transduction are also found among a large variety of receptors having another ligand.
Hormones reacting with cell surface receptors are of a varied nature. Typical examples are amino acid derivatives such as epinephrine or histamine, prostaglandins, various peptide hormones such as glucagon, insulin, gastrin, secretin, ACTH, LH, FSH, TSH, TRH, LHRH, vasopressin, IGF-I or II, EGF, somatotropin (growth hormone), prolactin, erythropoietin, EGF, and others.
These hormones all act by binding to their specific surface receptor, after which their specific signal is being transduced directly or by an intracellular signaling substance (a second messenger), leading to the specific action that is required of the cell.
The amount of functional (hormone) receptor on the cell surface is not constant. A receptor level is modulated up (up-regulation) or down (down-regulation), permitting the cell to respond to small changes in the hormone (ligand) level. The number of cell surface receptors is often down-regulated by endocytosis, whereby the sensitivity of the cell for the specific hormone (ligand) is reduced.
In general, when a ligand (hormone) binds to its receptor and results in a ligand-receptor complex, two phenomena occur. On the one hand, the signal transduction cascade is initiated, while on the other hand, the ligand-receptor complexes are brought in the cell by receptor-mediated endocytosis and the internalized ligand (hormone) is degraded. Internalization and degradation most likely terminate the hormone signal.
Some receptors recycle to the cell surface by exocytosis; however, even if they do, often a substantial fraction will be in the internal membrane compartments at any one time. Fewer receptors will be on the cell surface, available to bind extracellular hormone. Other receptors get degraded by proteolytic cleavage processes in the cell and thus do not, or only insignificantly, recycle to the cell surface, again reducing the number of available receptors on the cell surface.
Another way by which receptor availability on the cell surface is down-regulated is by removal, for example, by specific proteolysis, of the extracellular part that comprises parts of the binding site of a receptor. Such removal is in essence a physiological mechanism that serves to refresh the available receptors and replace them with new ones; however, it again is a factor in reducing receptor availability.
As a consequence of fewer functional receptors being available on the cell surface, the hormone concentration necessary to induce the physiological response is higher and the sensitivity of the cell to the hormone is reduced. The susceptibility of a cell or tissue to the action of a hormone is, thus, among others, dependent on the number of functional receptors present at any given time on the surface of a cell. Even when ligands are circulating at a high concentration, these cannot result in sufficient activation when not enough receptors are present.
Many hormonal-related or other diseases would benefit from an up-regulation of hormone or ligand activity. In hormonal dysfunctioning, one often attempts to achieve such up-regulation simply by treating a patient with exogenous hormones; however, as explained above, such a treatment may not be effective due to the fact that the number of available surface receptors for that hormone are too low. This is often aggravated by the fact that higher hormone concentrations, enhance, by feed-back mechanisms, the further down-regulation of the specific receptor. Exogenous hormone therapy may then even be counterproductive because the patient becomes less susceptible to the hormone in question.
There is thus a need for pharmacological tools or medication that can up- or down-regulate the presence or signal transduction of ligand-specific proteins, such as transport proteins, enzymes, cytosolic receptors or receptors on the surface of cells, for example, to result in a patient responding better to hormonal therapy or to provide the cells of the patient with a higher sensitivity to an endogenous hormone or other ligand.